Depression is characterize behaviorally by depressed mood, inability to experience pleasure, withdrawal of interest, and feelings of worthlessness which can often result in a debilitating quality of life, as well as suicide in many cases. Despite the significant advances that have been made in neurobiology and neuropharmacology of antidepressants, the molecular mechanisms underlying the actions antidepressant treatment have not been identified. Although the acute action of most antidepressants occurs via inhibition of the reuptake or breakdown 5-HT and NE, increased synaptic levels of these monoamines alone cannot account for the therapeutic action of antidepressants. Recent studies have shown that chronic antidepressant treatment (ADT) alters gene expression, especially components of cAMP signal transduction cascade. The delay in the therapeutic effects of ADT coincides with changes in gene expression in intracellular pathways, and it is thought that these changes mediate the therapeutic effects of antidepressants. It is known that stress and antidepressants have opposing actions on neuronal growth and vulnerability, in part due to the opposing effects on expression of neurotrophic factors. We hypothesize that stress and antidepressant administration have reciprocal changes in gene expression profiles. The aim of this R21 Exploratory Grant is to characterize the gene expression profiles to different classes of ADT, including 5-HT and norepinephrine selective reuptake inhibitors and ECS, and compare these profiles with changes observed with stress. It is however necessary to distinguish between acute and chronic alterations in response to ADT as only chronic ADT has been shown to possess therapeutic effects. This can be accomplished by comparing expression profiles by microarray analysis at various time points after and ADT. Gene expression changes will be characterized in the hippocampus and dentate gyrus of rat brain. This will increase our understanding of the mechanisms underlying the actions of antidepressant treatment and could lead to novel therapeutic targets. The results from these studies should lead to an ROl proposal aimed at extending these findings. Briefly, further studies would involve modulating the expression of genes identified by viral-mediated expression of genes in discrete brain regions and generation of transgenic mice, for study in behavioral models of stress and depression.